The present proposal is a comprehensive approach to the study of the hyperglycemic syndrome in the genetically obese (C57 B1/6J, ob/ob) mouse. It is hoped to gain better understanding of the relationships of the regulatory factors which determine the metabolic condition necessary to produce the tremendous obesity and hyperglycemia in the ob/ob mouse. Given the prevailing view of the literature and their own data, the present project emphasizes two major areas of regulation of the metabolism of glucose in the genetically obese mouse: (a) peripheral, cellular glucose utilization and (b) the role of central nervous glucoregulatory factors. Since catecholamines may be implicated as mediators at both of these sites, study of their involvement in glucoregulation in the obese mouse becomes particularly important. In its approach, this project concentrates on hepatic, adipose tissues and muscle cell responses to peripheral, adrenal regulators (catecholamines and glucocorticoids) and central regulators (hypothalamic neuroendocrine and autonomic influences). Therefore, particular attention will be directed towards two pituitary hormones (ACTH and growth hormone) and towards parasympathetic and sympathetic central nervous mechanisms that regulate pancreatic insulin and glucagon secretion. The experimental approach will include monitoring of parameters of glucose utilization (size of plasma glucose pool, glucose clearance from plasma, incorporation of glucose carbon into metabolites, etc.). Availability of these data as well as their analysis by sophisticated computer-based statistical techniques can be expected to yield a comprehensive view of the regulation in the ob/ob mouse of genetic obesity and its relationship to carbohydrate metabolism in this animal model. Students participating in this project under the MBRS program will be instructed by Project Assistants in chemical and biological skills as well as in the specific techniques (small animal surgery, radioisotope use, tissue sampling and chemical analysis, statistical data analysis) necessary for conduct of experiments under the project.